How to become a great medicinal chemist? (part two)

Mark A. Murcko combines his observations and experiences, summarizing the characteristics of many great medicinal chemists have in accordance with the two categories of “general” and “professional”, hoping to give aspirations to the field of medicinal chemistry.

Managing the nature of the compound

A great medicinal chemist’s gaze is not limited to the efficacy of the drug, but rather to the overall characteristics of the drug. At the same time, they are not limited to various rules, through experimental data to improve the parameters of the compound, such as molecular weight, structural complexity, lipophilic and so on. If optimized in the right direction, active compounds that do not seem to be a drug may also surprise.

HCV encodes at least 10 mature proteins, and non-structural protein 5A (NS5A) is one of its important proteins, and is also an important target for anti-HCV drugs. The candidate compounds found by medicinal chemists are somewhat “anti-conventional”, with molecular weights of up to 750-900 and a logP of 8, which has made some pharmaceutical companies somewhat embarrassed. However, there are still some teams who are brave enough to face the challenge and successfully market their drugs, such as daclatasvir and ledipasvir, by optimizing the structure.

Consider the three-dimensional structure

With the development of various technologies, drug designers can now easily obtain protein structures. But even if it is not, drug chemists have been contemplating the structure of compounds in three-dimensional space in their minds. How do they look, in water, and in lipids? Is there any difference between extracellular and intracellular? Does it change compared to the free state after binding to the target?

Prepare “Plan B”

Unexpectedly, drug research and development is a systematic project, and problems in any part of pharmacokinetics, drug toxicity, compound synthesis, drug production, intellectual property, etc., will have serious consequences. There is a high-quality, new structure of alternative compounds that are undoubtedly the best contingency plan. For example, at the beginning of Relay Therapeutics, team members consciously set out to discover many different types of chemical structures for three reasons: to maximize access to molecules with good bioavailability; to protect their work more broadly; to verify that they are constructed a drug discovery platform. In the first year, Relay’s team discovered more than a dozen compounds with nanomolar bioactivity, enabling the team to quickly move to clinical development.

Not worrying about intellectual property issues

Medicinal chemists must pay attention to patents. Sometimes, a number of companies aiming at “hot targets” in a bee-like project will lead to drug discovery around similar molecules, and patent homogenization competition is serious. But don’t forget that the “chemical space” is very large, and researchers are enough to jump out of existing patent restrictions and discover other drug molecules. There are sometimes many drug molecules targeting the same target, especially some drugs that follow the trend. Most of them have a common structure, but drug chemists can still retain their own characteristics and find unique “corners” in the “chemical space”. “By optimizing by target, each molecule has its own unique advantages.”